1. Field of the Invention
This invention relates to compositions that bind to FKBP proteins and to their use for treating neurological diseases. The invention also relates to methods of treating neurological diseases with these compositions.
2. Description of the Related Art
The diseases treated by compounds or compositions of the invention are major health problems and they are poorly addressed by current therapies. Patients seek medical attention after the disease or traumatic injury that has resulted in damage to the brain or peripheral nervous system. Drug treatments are available which offer symptomatic treatment for Parkinson's or Alzheimer's disease (e.g. dopamine or acetylcholine replacement therapies, respectively).
Neurological diseases are associated with the death of or injury to neuronal cells. For example, the loss of dopaminergic neurons in the substantia nigra is believed to be the basis for Parkinson's disease. Although the molecular mechanism of neurodegeneration in Alzheimer's disease is yet to be established, inflammation and deposition of beta-amyloid protein and other such agents may compromise neuronal function or survival. In patients suffering from brain ischemia or spinal cord injuries, extensive neuronal cell death is observed. Currently, there are no satisfactory treatments for these diseases.
One approach to treating neurological diseases involves the use of drugs capable of inhibiting neuronal cell death. A more recent approach involves the promotion of nerve regeneration by drugs which stimulate neurite outgrowth.
Recently, small molecules have been shown to stimulate axonal outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neurite outgrowth may protect neurons from further degeneration, and accelerate the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [C. Dominique Toran-Allerand et al., J. Steroid Biochem. Mol. Biol., 56, pp. 169-78 (1996); and B. S. McEwen et al., Brain Res. Dev. Brain. Res., 87, pp. 91-95 (1995)]. The progress of Alzheimer's disease may be slowed in women who take estrogen. Estrogen is hypothesized to complement NGF (nerve growth factor) and other neurotrophins and thereby help neurons differentiate and survive.
It has been reported that compounds with an affinity for the FK506 binding protein (FKBP) also possess nerve growth stimulatory activity [Lyons et al., PNAS, 91, pp. 3191-3195 (1994)]. Many of these compounds also have immunosuppressive activity, which could be a deleterious side effect in treating a human subject having a neurological disease.
FK506 (Tacrolimus), an immunosuppressive drug which binds to FKBP12 and other FKBP proteins, has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al., Proc Nat. Acad. Sci. (1994)]. This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher, Nature, 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve [B. Gold et al., J. Neurosci., 15, pp. 7509-16 (1995)].
More recently, sub-classes of FKBP binding compounds which lack immunosuppressive activity have been disclosed for use in stimulating nerve growth [see for example U.S. Pat. Nos. 5,614,547; 5,696,135; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner et al., Proc. Natl. Acad. Sci. USA, 94, pp. 2019-23 (1997); and G. S. Hamilton et al., Bioorg. Med. Chem. Lett., 7, pp. 1785-90 (1997)]. These compounds supposedly avoid certain unwanted side effects of immunosuppressive FKBP binding compounds but still bind to FKBP and alter its functioning.
Some compounds bearing a similarity to those of the present invention are disclosed in a published patent application, US 2002/0052410 A1 (published May 2, 2002). However, that application does not disclose or suggest the compounds of the present invention.
Furthermore, other compounds bearing a similarity to those of the present invention have been disclosed in another published patent application, US 2002/0052372 A1 (published May 2, 2002). However that application also fails to disclose or suggest the compounds of the present invention.